Copper(II)-bisoxazoline-catalysed asymmetric Diels-Alder reactions of α-thioacrylates

Article abstract of DOI:10.1002/1099-0690(200008)2000:16<2939::AID-EJOC2939>3.0.CO;2-K

A range of C₂-symmetric, chiral Cu(II) · bisoxazoline complexes were tested as catalysts for the asymmetric Diels - Alder cycloaddition between cyclopentadiene and a range of α-sulfenylacrylates. The optimum acrylate was ethyl α-phenyl-thioacrylate and the optimum catalyst was the bisoxazoline derived from phenylalanine which, upon complexation with Cu(SbF₆)₂, gave the cycloadducts in 92% yield, 88% de and > 95% ee for the endo product. The α-phenylthio ester moiety was easily converted into a carbonyl group furnishing (1S,4S)-norbornenone with high enantioselectivity. Attempts to improve the diastereoselectivity by changing the bite angle of the ligand were unsuccessful. An attempt is made to rationalise our findings in terms of the transition-state structure of the ligand-metal-dienophile complex.

Full text of DOI:10.1002/1099-0690(200008)2000:16<2939::AID-EJOC2939>3.0.CO;2-K

FULL PAPER
Copper(II)-Bisoxazoline-Catalysed Asymmetric Diels؊Alder Reactions of
α-Thioacrylates
Varinder K. Aggarwal,*[a] D. Elfyn Jones,[a] and Ana M. Martin-Castro[a]
Keywords: Cycloadditions / α-Phenylthioacrylates / Bisoxazolines / Copper / Asymmetric catalysis
A range of C2-symmetric, chiral CuII·bisoxazoline complexes
were tested as catalysts for the asymmetric Diels−Alder
cycloaddition between cyclopentadiene and a range of α-sul-
fenylacrylates. The optimum acrylate was ethyl α-phenyl-
thioacrylate and the optimum catalyst was the bisoxazoline
derived from phenylalanine which, upon complexation with
Ͼ95% ee for the endo product. The α-phenylthio ester moiety
was easily converted into carbonyl group furnishing
(1S,4S)-norbornenone with high enantioselectivity. Attempts
to improve the diastereoselectivity by changing the bite
angle of the ligand were unsuccessful. An attempt is made
to rationalise our findings in terms of the transition-state
a
Cu(SbF6)2, gave the cycloadducts in 92% yield, 88% de and structure of the ligand−metal−dienophile complex.
Introduction
The asymmetric DielsϪAlder reaction using catalytic
amounts of chiral Lewis acids has emerged as a powerful
strategy in asymmetric synthesis.[1Ϫ4] A vast array of metals,
ligands and dienophiles have been studied in this reaction
and, generally, the most successful systems involve chiral
ligands capable of bidentate chelation to a metal centre, to-
gether with dienophiles capable of two-point binding to the
metalϪligand complex. Such systems result in a reduction
of the number of accessible conformations of the
Scheme 1. Proposed strategy for asymmetric DielsϪAlder reaction
dienophileϪmetalϪligand complex thereby enhancing the
enantioselectivity.[5Ϫ7]
We have been interested in developing ketene equivalents
for DielsϪAlder reactions and have therefore sought dien-
ophiles that could be easily converted into carbonyl com-
Results and Discussion
pounds. Initially, we utilised bis-sulfoxides of ketene
We screened a range of bisoxazolines at various temper-
thioacetals as chiral ketene equivalents,[8] but this auxiliary-
atures and found that the phenyl-substituted ligand was op-
based approach is limited compared to catalytic methods.
timum (Scheme 2).[16]
We therefore considered the possibility of using chiral Lewis
We therefore concentrated our studies on the Ph substi-
acids with dienophiles in which the activating groups could
tuted ligand 7. The results of our studies into the effect of
be readily converted into a carbonyl functionality.
the acrylate structure,[17] reaction temperature and coun-
α-Thioacrylates seemed an ideal choice as ketene equiva-
terion are presented in Table 1 and Scheme 3.
lents since it is known that such dienophiles undergo
It was found that the selectivity of the DielsϪAlder reac-
DielsϪAlder reactions with cyclopentadiene and that the
tion was highly dependent on the nature of the ester and
cycloadducts
can
be
readily
converted
into
sulfenyl substituents. Higher selectivity was obtained with
phenylthio- rather than methylthioacrylates (entries 1, 3),
and higher selectivity was also obtained with small or mod-
erately sized ester substituents [Me, Et, iPr ϾϾ tBu (entries
2, 3, 6, 8, 9)]. The tBu ester was much less reactive than the
other esters and the reaction had to be conducted at 0 °C
(entry 8). This, presumably, was the cause of the reduction
in enantioselectivity. Higher selectivity was obtained at
lower temperature (see entries 3 and 4) and the use of cat-
ionic complexes[13] led to high reactivity even at Ϫ78 °C
(entries 5, 7) as well as high exo/endo selectivity and high
enantioselectivity. The optimum reagents and conditions re-
quired ethyl α-phenylthioacrylate as dienophile, the cationic
norbornenones.[9Ϫ11] Such dienophiles may also act as two
point binders to appropriate metals through carbonyl and
sulfenyl coordination (Scheme 1). Copper bisoxazolines
were chosen as the metalϪligand system due to the known
ability of copper to bind to both sulfur and oxygen and due
to the success of such complexes in a range of transforma-
tions including DielsϪAlder reactions.[12Ϫ14] In this paper
we describe our complete studies in this area.[15]
[a]
Department of Chemistry, University of Sheffield,
Sheffield, S3 7HF, UK
Fax: (internat.) ϩ44-114/273-8673
E-mail: V.Aggarwal@sheffield.ac.uk
Eur. J. Org. Chem. 2000, 2939Ϫ2945
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0816Ϫ2939 $ 17.50ϩ.50/0
2939

V. K. Aggarwal, D. E. Jones, A. M. Martin-Castro
FULL PAPER
Scheme 2. Variation of bisoxazoline in DielsϪAlder reactions
Table 1. DielsϪAlder reactions of α-sulfenylacrylates with cyclopentadiene catalysed by Cu-bisoxazoline complex 8 (Scheme 3)
Dienophile
Entry
R
RЈ Metal catalyst[a]
Time
Temp
(°C)
Yield
exo:endo[b]
ee[c]
1
2
3
4
5
6
7
8
9
1
2
3
3
3
4
4
5
6
Et
Me Cu(OTf)2
Ph Cu(OTf)2
Ph Cu(OTf)2
Ph Cu(OTf)2
6h
Ϫ40
Ϫ40
Ϫ40
Ϫ78
Ϫ78
Ϫ40
Ϫ78
0
53
44
50
76
92
70
90
91
92
1:2.4
1:3.7
1:4
40
Me
Et
6h
84
6h
80
Et
9h
1:7
Ͼ95
Ͼ95
85
[d]
Et
Ph CuBr2/AgSbF6
Ph Cu(OTf)2
1h
1:15
1:2.3
1:5
1:2.5
1:13
iPr
4h
[d]
[d]
iPr
Ph CuBr2/AgSbF6
Ph Cu(OTf)2
Ph CuBr2/AgSbF6
2.5h
5.5h
2h
81
tBu
CH2CF3
26
Ϫ78
Ͼ95
[a]
[b]
20 mol-% Cu(OTf)2, 30 mol-% bisoxazoline 7, 1 equiv. of dienophile and 4 equiv. of cylopentadiene. Ϫ
Determined by NMR
[c]
integration of crude reaction mixtures. Ϫ Determined by NMR integration in presence of PirkleЈs reagent, (R)-(Ϫ)-2,2,2-trifluoro-1-
(9-anthryl)ethanol. Ϫ 10 mol-% of CuBr2/AgSbF6, 10 mol-% bisoxazoline 7, 1 equiv. dienophile and 4 equiv. cylopentadiene.
[d]
stable than the ethyl acrylate 3, which has to be used imme-
diately after preparation to avoid polymerisation. In the
event, neither 3 nor 6 proved to be reactive enough with
furan under our optimum conditions, even at higher tem-
peratures (up to 0 C): whilst 3 polymerised, 6 could be re-
isolated.
A transition state involving bidentate binding of the dien-
ophile through sulfur and the carbonyl oxygen to a square
planar or distorted square planar CuII complex[13,14,18Ϫ21]
may be proposed to rationalise the enantio- and diastereo-
selectivities. However, the high enantioselectivity observed
is perhaps surprising as the alkene of the dienophile lies
close to the C2 axis of the metal catalyst where it encounters
the minimum steric influence from the phenyl groups of the
oxazoline moiety. The fact that high enantioselectivity is
achieved in this situation is highly unusual as such selectiv-
ities are only usually observed when the prochiral carbon
Scheme 3. Variation of acrylate in DielsϪAlder reactions
or group is placed directly above one of the oxazoline sub-
stituents. Indeed, very few examples exist where the pro-
phenyl-substituted bisoxazoline-copper complex, and a re- chiral carbon is positioned on or close to the C2 axis of the
action temperature of Ϫ78 °C in CH2Cl2 (entry 5); under ligand.[22,23] In our case we believe that the substituent on
these conditions good diastereo- and essentially complete sulfur plays a major role in controlling enantioselectivity.
enantioselectivity was observed.
We believe there is very high diastereoselectivity in forma-
The ethyl acrylate 3 reacted rapidly at Ϫ78 C with cyclo- tion of the dieneophileϪmetalϪoxazoline complex (only
pentadiene and so we considered the possibility of using one of the two enantiotopic lone pairs of the sulfur atom
less-reactive dienes, in particular furan. As we recognised binds to the copper) and it is the orientation of the sulfur
that furan is an especially unreactive diene we also prepared substituent which controls the facial attack on the dienoph-
the more reactive dienophile, trifluoroethyl acrylate 6. In- ile (Figure 1). This substituent is forced below the plane of
terestingly, the trifluoroethyl acrylate 6 is substantially more the complex, and when this group is large it effectively
2940
Eur. J. Org. Chem. 2000, 2939Ϫ2945

Copper(II)-Bisoxazoline-Catalysed Asymmetric DielsϪAlder Reactions of α-Thioacrylates
FULL PAPER
blocks the Si face of the dienophile and therefore forces the
diene onto the Re face. Increasing the size of the sulfur
substituent may not only increase the diastereoselectivity of
the complexation but also the subsequent facial selectivity
of the dienophile. From analysis of molecular models, the
opposite enantiomer would be expected if the dienophile
was bound to Cu in a tetrahedral arrangement. This pro-
vides further circumstantial evidence for a square planar
complex. It is also possible that endo/exo selectivity is influ-
enced not only by secondary orbital interactions but also
by steric interaction of the cyclopentadiene with the Ph sub-
stituent on the oxazoline ring which disfavours the exo ap-
proach.
Scheme 4. Conversion of DielsϪAlder adduct into norbornenone
rived from the cycloadduct. In order to increase the endo/
exo selectivity, we considered varying the bisoxazoline li-
gand under our ‘‘optimised’’ conditions. Part of our in-
spiration came from the work of Davies et al. at
Merck.[18,19,25] They noted a marked improvement in endo
enantioselectivity and endo/exo selectivity in DielsϪAlder
reactions of cyclopentadiene with acrylimides catalysed
by Cu(OTf)2-bisoxazoline when the ‘‘bite angle’’ of the
ligands was increased. The bite angle was varied by chan-
ging the substituents on the bridging methylene group of
the bisoxazoline (e.g. 17؊19; largest bite angle was ob-
served with the spirocyclopropyl ligand 17). A similar ef-
fect was observed by Ghosh[26] in a related series of reac-
tions in which the methylene bridged ligand 20 gave much
improved selectivity compared with its dimethyl-substi-
tuted counterpart 7. The bite angle of ligand 20 is larger
than that of 7 due to a reduced steric compression[27] ef-
fect which, in the latter case, causes an angular contrac-
tion. Increasing the bite angle of the ligand should result
in the metal being forced closer to the ligand centre and
any dienophile bound to the metal will then also be
brought closer to the substituents of the chiral ligand and
will experience increased influence from the ligand. This
accounts for the improvements in stereoselectivity ob-
served.
Figure 1. Proposed transition state for DielsϪAlder reaction
The size of the ester group of the dienophile is critical.
An excessively bulky group may inhibit two-point binding
of the dienophiles, as seems to be the case with the tert-
butylester such that no reaction occurs at low temperatures.
At higher temperatures, low selectivity is observed perhaps
because of a more loosely bound complex.
Conversion of the α-phenylthioester to a carbonyl group
was initially problematic. Hydrolysis of the ester into the
acid occurred efficiently but required high temperatures and
an appropriate solvent to ensure that both the ester and
base had dissolved (Scheme 4). Interestingly, the trifluoroe-
thyl ester 14 was hydrolysed under the same conditions in
less than five minutes. Whilst ester hydrolysis proceeded
smoothly, all attempts to convert the α-phenylthioacid 16
to the carbonyl group using NCS was unsuccessful
(Scheme 4). This reagent has previously been used to con-
vert an α-methylthioacid to a carbonyl group, but we be-
lieve that the lower nucleophilicity of the phenylthio group
is the problem.[9]
We were eventually successful using a different strategy:
instead of activating the sulfide we activated the acid. Thus
reacting the α-phenylthioacid with diphenylphosphoryl az-
ide[24] we obtained the corresponding ketone 15 directly in
high yield and with 88% ee (Scheme 4). The lower enanti-
oselectivity observed for 15 is due to the presence of the
exo isomer in 16. As only a small amount of the exo isomer
was present in 16, it indicates that this isomer must have
been formed with high, but opposite, enantioselectivity with
respect to the major endo isomer.
The results of our studies with different bisoxazoline li-
gands (Figure 2) are presented in Table 2.
Whilst we were satisfied with the enantioselectivity of
the endo cycloadduct, the endo/exo selectivity was some-
what disappointing, especially as this led to a lowering of
the attainable enantiomeric excess of norbornenone de- Figure 2. Other bisoxazolines tested
Eur. J. Org. Chem. 2000, 2939Ϫ2945
2941

V. K. Aggarwal, D. E. Jones, A. M. Martin-Castro
FULL PAPER
benzophenone; dichloromethane, triethylamine and DMF were dis-
tilled from calcium hydride; cyclopentadiene was cracked and dis-
tilled immediately prior to use. Other commercially available re-
agents were used as received from the supplier. Acrylates (1؊5)
were prepared as described in the literature.[17,34] NMR spectra
were recorded on a Bruker AM250 instrument in CDCl3 unless
otherwise stated and are referenced to the appropriate solvent sig-
nal. Mass spectra were obtained on KRATOS MS25, MS80 and
VG Prospec instruments. Infra red spectra were obtained on a
PerkinϪElmer PE684 instrument. GC analysis of norbornenone
was achieved on a PerkinϪElmer PE Autosystem XL instrument
using an α-cyclodextrin capillary column (Supelco Alphadex 120
fused silica capillary column column, length 30 m, 0.25 mm id.,
0.25 µm film thickness) at 70 °C isothermal, hydrogen carrier gas
(20psi); retention times 8.8 min and 9.1 min. The bisoxazolines
were purchased from Aldrich and were used without further puri-
fication.
Table 2. Effect of varying ligand on selectivity of DielsϪAlder reac-
tion between cyclopentadiene and ethyl α-phenylthioacrylate
Entry[a]
Ligand
Yield (%)
exo:endo[b]
endo ee (%)[c]
1
2
3
4
5
6
7
92
75
52
87
76
81
1:15
1:2.3
1:3
Ͼ95
0
17
18
19
20
21
68[d]
0
1:2
1:3.8
1:11
56
Ͼ95
[a]
10 mol-% of CuBr2/AgSbF6, 10 mol-% bisoxazoline, 1 equiv.
ethyl α-phenylthioacrylate and 4 equiv. cylopentadiene. Ϫ [b] Deter-
mined by NMR integration of crude reaction mixtures. Ϫ [c] Deter-
mined by NMR integration in the presence of PirkleЈs reagent, (R)-
[d]
(Ϫ)-2,2,2-trifluoro-1-(9-anthryl)ethanol. Ϫ
The endo cycload-
duct shows the opposite absolute configuration to the other ex-
amples.
Entry 1 is our usual conditions with ligand 7. Changing
from a dimethyl- to a spirocyclopentyl substituent on the
methylene bridge (ligand 21) should increase the ligand bite
angle slightly.[25] This resulted in a small decrease in endo/
exo selectivity whilst the endo enantioselectivity remained
excellent (entry 6). A larger increase in bite angle should
occur with ligand 20 (entry 5). However, contrary to what
2Ј2Ј2Ј-Trifluoroethyl 2-Bromopropionate:[36] To an ice-cooled stirred
solution of 2-bromopropionyl chloride (5.10 g, 29.7 mmol) in
dichloromethane (30 mL) was added dropwise 2,2,2-trifluoroe-
thanol (3.13 g, 31.3 mmol) and freshly distilled triethylamine
(4.56 mL). The mixture was stirred at room temperature for 16 h.
Then it was washed with water and the two layers were separated.
The aqueous phase was extracted with dichloromethane (2 ϫ
we had expected, this resulted in a greatly diminished ste- 50 mL). The combined organic extracts were dried (Na2SO4) and
evaporated. The resulting solid was purified by flash chromato-
graphy (dichloromethane) giving 5.83 g of the title compound (83%
yield). Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 1.87 (d, J ϭ 7.0 Hz, 3
H), 4.44 (q, J ϭ 7.0 Hz, 1 H), 4.55 (dq, J ϭ 8.2, 0.9 Hz, 2 H).
reoselectivity both in terms of endo/exo selectivity and en-
antioselectivity.
No clear trend between the diastereoselectivity and/or en-
antioselectivity with the bite angle was observed with the
indanol-derived ligands 17؊19 (entries 2Ϫ4). Indeed, the
2Ј2Ј2Ј-Trifluoroethyl 2-Phenylthiopropionate: KOH pellets (0.99 g,
ligands having largest and smallest bite angles (17 and 19, 16.0 mmol) were added to a solution of thiophenol (1.79 g,
16.2 mmol) in tetrahydrofuran (15 mL). The mixture was stirred
under argon at room temperature until all the pellets had dissolved
(ca. 2 h). A solution of 2-bromo-2Ј2Ј2Ј-trifluoroethylpropionate
(3.53 g, 15.0 mmol) in tetrahydrofuran (10 mL) was added drop-
wise to the ice-cooled white reaction mixture, with continuous stir-
ring. Upon completion of the addition the ice bath was removed
and the mixture was stirred at room temperature for 18 h. Then
water (20 mL) was added and the two layers were separated. The
aqueous layer was extracted with dichloromethane (4 ϫ 50 mL),
the combined organic extracts were dried (Na2SO4), and the solv-
respectively) both gave racemic products with low diaster-
eoselectivity (entries 2 and 4), whilst the ligand with inter-
mediate bite angle (18) gave moderate selectivity, but now
in favour of the opposite enantiomer. The lack of selectivity
observed with the indanol-derived bisoxazolines was sur-
prising.
Reversal of the sense of induction in certain reactions
catalysed by metal-bisoxazoline complexes, wherein the
only variable that changes is the pendant substituent on the
oxazoline ring, is well documented.[20,28Ϫ33] This has been ent was evaporated to give the title compound as a colourless oil
(3.01 g, 76% yield); Ϫ IR (thin film): νmax ϭ 1755 cmϪ1. Ϫ 1H
NMR (250 MHz, CDCl3): δ ϭ 1.52 (d, J ϭ 7.0 Hz, 3 H), 3.85 (q,
attributed either to a change in the metal geometry from
square planar to tetrahedral[20,29Ϫ33] or to the extent of dis-
J ϭ 7.0 Hz, 1 H), 4.42 (dq, J ϭ 8.2, 1.8 Hz, 2 H), 7.28Ϫ7.35 (m, 3
tortion away from planarity of the square planar com-
H), 7.41Ϫ7.53 (m, 2 H). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ
plexes.[28] However, because of the low selectivity observed
16.9, 44.6, 60.7 (q, J ϭ 36.9 Hz), 122.8 (q, J ϭ 277.5 Hz), 128.4,
with the indanol series of bisoxazolines, it is not possible to
comment on which of these is occurring.
In conclusion, we have developed a catalytic asymmetric
DielsϪAlder cycloaddition reaction of α-thioacrylates with
cyclopentadiene, achieving good levels of endo selectivity
and excellent enantioselectivity, and converted the cycload-
ducts into norbornenone in good yields and high enantiose-
lectivity. Attempts to increase the endo/exo selectivity by
128.9, 132.2, 133.3, 171.0. Ϫ MS: m/z (%) ϭ 264 (71) [Mϩ], 218
(100), 185 (9), 154 (11), 137 (73), 109 (76), 65 (24). Ϫ HR-MS
(C11H11F3O2S): calcd. 264.0432; found 264.0438.
2Ј2Ј2Ј-Trifluoroethyl 2-(Phenylsulfinyl)propionate: To an ice-cooled
stirred solution of 2Ј2Ј2Ј-trifluoroethyl 2-phenylthiopropionate
(1.06 g, 4.03 mmol) in diethyl ether (10 mL) was added dropwise a
solution of m-chloroperoxybenzoic acid (1.23 g; 56Ϫ86%) in di-
ethyl ether (10 mL) over 10 minutes. The resulting solution was
stirred at room temperature for 5 h. The solvent was evaporated
giving a white solid. This solid was dissolved in dichloromethane
(50 mL) and the organic solution was washed with sodium thiosulf-
ate (aq. ca. 50%, 20 mL) and saturated aqueous NaHCO3 solution.
The organic layer was dried (Na2SO4) and evaporated. The re-
sulting solid was purified by flash chromatography (petroleum
ether 40Ϫ60 fraction/ethyl acetate 1:2) giving 125 mg of sulfoxide
changing the bite angle of the bisoxazolines were ulti-
mately unsuccessful.
Experimental Section
All reactions were performed in oven dried glassware under dry
argon unless otherwise stated. THF was distilled from potassium/
2942
Eur. J. Org. Chem. 2000, 2939Ϫ2945

Copper(II)-Bisoxazoline-Catalysed Asymmetric DielsϪAlder Reactions of α-Thioacrylates
A (Rf ϭ 0.41), 89 mg of sulfoxide B (Rf ϭ 0.36) and 469 mg of A
the crude material purified by flash column chromatography on
FULL PAPER
ϩ B mixture (61% overall yield). Ϫ IR (thin film): νmax ϭ 1756 silica gel (petroleum ether 40Ϫ60 fraction/dichloromethane 1:1)
1
cmϪ1. Ϫ H NMR (250 MHz, CDCl3) isomer A: δ ϭ 1.50 (d, J ϭ giving the title product as a very pale yellow oil (1.81 g, 92%). Ϫ
7.0 Hz, 3 H), 3.63 (q, J ϭ 7.0 Hz, 1 H), 4.41 (m, 2 H), 7.51Ϫ7.59
IR (thin film): νmax ϭ 1720cmϪ1. Ϫ 1H NMR (250 MHz, CDCl3):
(m, 3 H), 7.59Ϫ7.66 (m, 2 H); isomer B: δ ϭ 1.42 (d, J ϭ 7.3 Hz, δ ϭ (endo) 1.10 (t, J ϭ 7.5 Hz, 3 H), 1.55Ϫ1.67 (m, 1 H), 1.89 (dd,
3 H), 3.89 (q, J ϭ 7.3 Hz, 1 H), 4.41 (m, 2 H), 7.49Ϫ7.65 (m, 5 J ϭ 12.5, 3.1 Hz, 1 H), 2.13Ϫ2.22 (m, 1 H), 2.88Ϫ2.96 (m, 1 H),
H). Ϫ 13C NMR (62.9 MHz, CDCl3) isomer A: δ ϭ 9.0, 61.1 (q, 3.03Ϫ3.10 (m, 1 H), 3.84Ϫ4.10 (m, 2 H), 5.91 (dd, J ϭ 5.6, 2.5 Hz,
J ϭ 37.2 Hz), 64.7, 124.5, 124.7 (q, J ϭ 277.5 Hz), 129.6, 133.0, 1 H), 6.21 (dd, J ϭ 5.6, 2.5 Hz, 1 H), 7.25Ϫ7.39 (m, 3 H),
141.0, 167.0; isomer B: δ ϭ 9.3, 60.8 (q, J ϭ 37.2 Hz), 63.2, 124.7
7.41Ϫ7.53 (m, 2 H); (exo) 1.19 (t, J ϭ 7.5 Hz, 3 H), 1.24Ϫ1.30 (m,
(q, J ϭ 277.5 Hz), 124.8, 129.1, 132.0, 139.8, 166.5. Ϫ MS: m/z 1 H), 1.34 (dd, J ϭ 12.5, 3.1 Hz, 1 H), 1.60Ϫ1.68 (m, 1 H),
(%) ϭ (isomer A) 280 (39) [Mϩ], 156 (7), 139 (6), 125 (100), 83 2.88Ϫ2.95 (m, 1 H), 3.38Ϫ3.44 (m, 1 H), 3.84Ϫ4.10 (m, 2 H),
(10), 77 (22); (isomer B) 280 (30) [Mϩ], 156 (16), 139 (14), 125 6.25Ϫ6.38 (m, 2 H), 7.25Ϫ7.39 (m, 3 H), 7.42Ϫ7.53 (m, 2 H). Ϫ
(100), 83 (11), 77 (26). Ϫ HR-MS (C11H11F3O3S): calcd. 280.0381;
found (isomer A) 280.0390; (isomer B) 280.0390. Ϫ C11H11F3O3S: 49.7, 60.7, 60.9, 128.6, 128.9, 132.5, 134.1, 135.7, 139.8, 172.9. Ϫ
13C NMR (62.9 MHz, CDCl3): δ ϭ (endo) 14.0, 38.9, 42.7, 47.2,
calcd. C 47.14, H 3.96; found C 46.99, H 3.93.
HR-MS (C15H18O2S): calcd. 262.0871; found 262.0876.
Ethyl 2-(Methylthio)bicyclo[2.2.1]hept-5-ene-2-carboxylate (9): IR
(thin film): νmax ϭ 1720cmϪ1. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ
(endo) 1.26 (t, J ϭ 6.0 Hz, 3 H), 1.49Ϫ1.68 (m, 2 H), 1.77 (dd, J ϭ
12.5, 3.0 Hz, 1 H), 2.04 (dd, J ϭ 12.5, 3.0 Hz, 1 H), 2.09 (s, 3 H),
2.84Ϫ2.90 (m, 1 H), 3.09Ϫ3.13 (m, 1 H), 3.52 (s, 3 H), 4.12 (q, J ϭ
6.0 Hz, 2 H), 6.00 (dd, J ϭ 8.0, 3.5 Hz, 1 H), 6.21 (dd, J ϭ 8.0,
3.5 Hz, 1 H); (exo) 1.13 (dd, J ϭ 12.5, 3.0 Hz, 1 H), 1.31 (t, J ϭ
6.0 Hz, 3 H), 1.49Ϫ1.68 (m, 2 H), 2.17 (s, 3 H), 2.58 (dd, J ϭ 12.5,
3.0 Hz, 1 H), 2.90Ϫ2.95 (m, 1 H), 3.09Ϫ3.13 (m, 1 H), 4.22 (q, J ϭ
6.0 Hz, 2 H), 6.11 (dd, J ϭ 8.0, 3.5 Hz, 1 H), 6.29 (dd, J ϭ 8.0,
3.5 Hz, 1 H). Ϫ MS: m/z (%) ϭ 212 (72) [Mϩ], 146 (100), 139 (17),
100 (56), 91 (48) 73 (44), 66 (67). Ϫ HR-MS (C11H16O2S): calcd.
212.0871; found 212.0876.
2Ј2Ј2Ј-Trifluoroethyl 2-Phenylthioacrylate (6): To a solution of
2Ј2Ј2Ј-trifluoroethyl (2-phenylsulfinyl)propionate (1:1 mixture of
diastereomers; 411 mg, 1.47 mmol) in anhydrous dichloromethane
(10 mL) under argon, was added a solution of trifluoroacetic an-
hydride (434 mg, 2.07 mmol) in dichloromethane (0.5 mL). The
mixture was stirred at room temperature for 2 h. The solvent was
evaporated and the crude material was purified by flash chromato-
graphy (petroleum ether 40Ϫ60 fraction/dichloromethane 3:2) to
afford the title compound as a very pale yellow oil (262 mg, 68%).
Ϫ IR (thin film): νmax ϭ 1749 cmϪ1. Ϫ 1H NMR (250 MHz,
CDCl3): δ ϭ 4.55 (q, J ϭ 8.2 Hz, 2 H), 5.43 (d, J ϭ 0.6 Hz, 1 H),
6.43 (d, J ϭ 0.6 Hz, 1 H), 7.36Ϫ7.2 (m, 3 H), 7.43Ϫ7.50 (m, 2 H). It
was not possible to obtain further data as the acrylate decomposed.
Methyl 2-(Phenylthio)bicyclo[2.2.1]hept-5-ene-2-carboxylate (10):
General Procedure for the Preparation of the Catalyst. ؊ Cu(OTf)2/
(S)-(؊)-2,2Ј-Isopropylidene-bis(4-phenyl)-2-oxazoline: A solution of
the bisoxazoline (65 mg, 0.19 mmol) in dichloromethane (3.0 mL)
was added to a flask containing copper(II) triflate (62 mg,
0.17 mmol) and the resulting blue-green solution stirred at room
temperature for 3 h.
1
IR (thin film): νmax ϭ 1730cmϪ1. Ϫ H NMR (250 MHz, CDCl3):
δ ϭ (endo) 1.54Ϫ1.66 (m, 2 H), 1.88 (dd, J ϭ 12.5, 2.0 Hz, 1 H),
2.06 (dd, J ϭ 12.5, 2.0 Hz, 1 H), 2.88Ϫ2.95 (m, 1 H), 3.00Ϫ3.05
(m, 1 H), 3.52 (s, 3 H), 5.90 (dd, J ϭ 5.0, 2.0 Hz, 1 H), 6.22 (dd,
J ϭ 5.0, 2.0 Hz, 1 H), 7.26Ϫ7.36 (m, 5 H); (exo) 1.35 (dd, J ϭ
12.5, 2.0 Hz, 1 H), 1.54Ϫ1.66 (m, 1 H), 2.61 (dd, J ϭ 12.5, 2.0 Hz,
1 H), 2.88Ϫ2.95 (m, 1 H), 3.35Ϫ3.39 (m, 1 H), 3.56 (s, 3 H), 6.28
(dd, J ϭ 5.0, 2.0 Hz, 1 H), 6.35 (dd, J ϭ 5.0, 2.0 Hz, 1 H),
7.39Ϫ7.52 (m, 5 H). Ϫ MS: m/z (%) ϭ 260 (22) [Mϩ], 218 (11),
194 (100), 135 (98), 109 (26), 91 (38), 65 (19). Ϫ HR-MS
(C15H18O2S): calcd. 260.0871; found 260.0876.
CuBr2/AgSbF6/(S)-(؊)-2,2Ј-Isopropylidene-bis(4-phenyl)-2-oxa-
zoline: A solution of the bisoxazoline (66 mg, 0.20 mmol) in dichlo-
romethane (5.0 mL) was added to CuBr2 with a cannula and the
mixture stirred at room temperature for 3 h. Silver hexafluoroanti-
monate was weighed into a dry, round-bottomed flask fitted with
a magnetic stir bar. The flask was evacuated (0.01 Torr), gently
heated and then flushed with argon and this procedure was re-
peated three times. The orange brown solution of copper(II) brom-
ide/bisoxazoline was transferred to this flask with a cannula and
the mixture stirred at room temperature for 1 h with exclusion of
light giving a green solution of the desired complex plus precipit-
ated AgBr.
Isopropyl 2-(Phenylthio)bicyclo[2.2.1]hept-5-ene-2-carboxylate (12):
1H NMR (250 MHz, CDCl3): δ ϭ (endo) 1.00 (d, J ϭ 7.5 Hz, 3
H), 1.10 (d, J ϭ 7.5 Hz, 3 H),1.48Ϫ1.54 (m, 1 H), 1.83 (dd, J ϭ
12.5, 5.6 Hz, 1 H), 2.00 (dd, J ϭ 12.5, 5.6 Hz, 1 H), 2.06Ϫ2.13 (m,
1 H), 2.80Ϫ2.88 (m, 1 H), 2.97Ϫ3.02 (m, 1 H), 4.77 (septet, J ϭ
7.5 Hz, 1 H), 5.84 (dd, J ϭ 6.3, 3.1 Hz, 1 H), 6.14 (dd, J ϭ 6.3,
3.1 Hz, 1 H), 7.17Ϫ7.26 (m, 3 H), 7.32Ϫ7.44 (m, 2 H); (exo) 0.96
(d, J ϭ 7.5 Hz, 3 H), 1.08 (d, J ϭ 7.5 Hz, 3 H), 1.14Ϫ1.27 (m, 1
H), 1.29 (dd, J ϭ 12.5, 5.0 Hz, 1 H), 1.54Ϫ1.61 (m, 1 H), 2.57 (dd,
J ϭ 12.5, 5.0 Hz, 1 H), 2.80Ϫ2.88 (m, 1 H), 3.32Ϫ3.37 (m, 1 H),
4.82 (septet, J ϭ 7.5 Hz, 1 H), 6.20 (dd, J ϭ 6.3, 3.1 Hz, 1 H), 6.26
(dd, J ϭ 6.3, 3.1 Hz, 1 H), 7.17Ϫ7.26 (m, 3 H), 7.32Ϫ7.44 (m, 2 H).
General Procedure for the Diels؊Alder Cycloaddition of Thioacryl-
ates with Cyclopentadiene. ؊ Preparation of Ethyl 2-(Phenylthio)-
bicyclo[2.2.1]hept-5-ene-2-carboxylate (11): A solution of freshly
prepared 3 (1.49 g, 7.15 mmol) in dichloromethane (12.0 mL) was
cooled to Ϫ78 °C, then added with a cannula to a solution of
freshly cracked and distilled cyclopentadiene (0.70 g, 10.61 mmol)
in dichloromethane (8.0 mL), also cooled to Ϫ78 °C, and this solu-
tion stirred with cooling at Ϫ78 °C for 5 min. A solution of the CuII
catalyst prepared as above [20 mol-% Cu with Cu(OTf)2, 10mol-%
with Cu(SbF6)2], was cooled to Ϫ78 °C and the solution of cyclo-
pentadiene and dienophile added with a cannula. The green reac-
tion mixture was stirred at Ϫ78 °C for 2 h or until the reaction
had gone to completion. It was then allowed to warm to room
temperature and filtered through a small plug of silica gel washing
thoroughly with dichloromethane. The solvent was evaporated and
tert-Butyl 2-(Phenylthio)bicyclo[2.2.1]hept-5-ene-2-carboxylate (13):
1H NMR (250 MHz, CDCl3): δ ϭ (endo) 1.30 (s, 9 H), 1.63Ϫ1.67
(m, 1 H), 1.76 (dd, J ϭ 12.5, 3.1 Hz, 1 H), 2.15Ϫ2.20 (m, 1 H),
2.65 (dd, J ϭ 12.5, 3.1 Hz, 1 H), 2.89Ϫ2.95 (m, 1 H), 3.35Ϫ3.42
(s, 1 H), 6.28 (dd, J ϭ 12.5, 3.1 Hz, 1 H), 6.35 (dd, J ϭ 12.5, 3.1 Hz,
1 H), 7.15Ϫ7.23 (m, 3 H), 7.28Ϫ7.39 (m, 2 H); (exo) 1.32 (s, 9 H),
1.55Ϫ1.60 (m, 1 H), 1.83 (dd, J ϭ 12.5, 3.1 Hz, 1 H), 2.05 (dd, J
12.5, 3.1 Hz, 1 H), 2.13Ϫ2.16 (m, 1 H), 2.89Ϫ2.95 (m, 1 H),
3.01Ϫ3.05 (s, 1 H), 5.92 (dd, J ϭ 12.5, 3.0 Hz, 1 H), 6.24 (dd, J ϭ
12.5, 3.0 Hz, 1 H), 7.15Ϫ7.23 (m, 3 H), 7.28Ϫ7.39 (m, 2 H).
Eur. J. Org. Chem. 2000, 2939Ϫ2945
2943

V. K. Aggarwal, D. E. Jones, A. M. Martin-Castro
FULL PAPER
2Ј2Ј2Ј-Trifluoroethyl 2-(Phenylthio)bicyclo[2.2.1]hept-5-ene-2-carb-
oxylate (14): IR (thin film): νmax ϭ 1747cmϪ1. Ϫ 1H NMR
(250 MHz, CDCl3): δ ϭ 1.63 (m, 1 H), 2.00 (m, 2 H), 2.17 (m, 1
H), 2.96 (m, 1 H), 3.09 (m, 1 H), 4.08 (dq, J ϭ 12.6, 8.5 Hz, 1 H),
4.46 (dq, J ϭ 12.6, 8.5 Hz, 1 H), 5.92 (dd, J ϭ 5.8, 3.1 Hz, 1 H),
6.25 (dd, J ϭ 5.8, 3.1 Hz, 1 H), 7.29Ϫ7.51 (m, 5 H). Ϫ 13C NMR
(62.9 MHz, CDCl3): δ ϭ 39.0, 42.6, 47.1, 49.6, 60.4 (q, J ϭ
36.5 Hz), 122.8 (q, J ϭ 277.5 Hz), 128.8, 129.3, 133.7, 135.8, 136.6,
140.3, 171.3. Ϫ MS: m/z (%) ϭ 328 (11) [Mϩ], 262 (100), 135 (95),
109 (14), 91 (42), 77 (7), 65 (18). Ϫ HR-MS (C16H15F3O2S): calcd.
328.0745; found 328.0729.
Acknowledgments
We thank the EPSRC and Sheffield University for support. We
thank Ian Davies (Merck) for valuable discussions and for the do-
nation of ligands 17, 20, 21 and George Hynd for help in the pre-
paration of this manuscript.
[1]
W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1984, 23, 876.
H. B. Kagan, O. Riant, Chem. Rev. 1992, 92, 1007.
T. Oh, M. Reilly, Org. Prep. Proc. Int., 1994, 26, 129.
L. C. Dias, J. Braz. Chem. Soc., 1997, 8, 289.
D. A. Evans, E. J. Olhava, J. S. Johnson, J. M. Janey, Angew.
Chem. Int. Ed. 1998, 37, 3372.
E. J. Corey, D. Barnes-Seeman, T. W. Lee, Tetrahedron Lett.
1997, 38, 1699.
[2]
[3]
[4]
[5]
Preparation of 2-(Phenylthio)bicyclo[2.2.1]hept-5-ene-2-carboxylic
Acid (16): A solution of KOH in isobutyl alcohol (10% w/w, 30 mL)
was added to 11 (1.80 g, 6.57 mmol). The cloudy solution was
stirred at 100 °C for 28 h and then cooled to room temperature. The
resulting mixture was dissolved in water (100 mL) and the solution
extracted with dichloromethane (100 mL). The aqueous phase was
then acidified (conc. HCl) and extracted with dichloromethane (3
ϫ 100 mL). These extracts were combined and dried over magnes-
ium sulfate, and the solvent removed under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel (petroleum ether 40Ϫ60/acetone 2:1) giving the title com-
pound as a pale yellow crystalline solid (1.24 g, 77%). Ϫ m.p.
75Ϫ83 °C. Ϫ [α]2D2 ϭ Ϫ51.7 (c ϭ 0.1 in CHCl3) [ref. for the opposite
enantiomer:[37] [α]2D2 ϭ ϩ21 (c ϭ 0.67)]. Ϫ 1H NMR (250 MHz,
CDCl3): δ ϭ (endo) 1.49Ϫ1.59 (m, 1 H), 1.79Ϫ1.99 (m, 2 H),
2.07Ϫ2.14 (m, 1 H), 2.84Ϫ2.89 (m, 2 H), 2.89Ϫ2.96 (m, 1 H), 5.90
(dd, J ϭ 5.0, 1.9 Hz, 1 H), 6.16 (dd, J ϭ 5.0, 1.9 Hz, 1 H),
7.15Ϫ7.34 (m, 3 H), 7.34Ϫ7.45 (m, 2 H); (exo) 1.59Ϫ1.63 (m, 1
H), 1.79Ϫ1.99 (m, 2 H), 2.46Ϫ2.56 (m, 1 H), 2.89Ϫ2.96 (m, 2 H),
3.23Ϫ3.28 (m, 1 H), 6.13Ϫ6.20 (m, 1 H), 6.23Ϫ6.28 (m, 1 H),
7.15Ϫ7.35 (m, 3 H), 7.35Ϫ7.45 (m, 2 H). Ϫ 13C NMR (62.9 MHz,
CDCl3): δ ϭ (endo) 38.6, 42.8, 47.2, 49.3, 60.7, 128.8, 129.3, 132.2,
134.7, 140.1, 178.5. Ϫ MS: m/z (%) ϭ 246 (25) [Mϩ], 180 (98), 135
(100), 109 (12), 91 (45), 77 (15), 66 (20). Ϫ HR-MS (C14H14O2S):
calcd. 246.0715; found 246.0707.
[6]
[7]
E. J. Corey, D. Barnes-Seeman, T. W. Lee, Tetrahedron Lett.
1997, 38, 4351.
V. K. Aggarwal, J. Drabowicz, R. S. Grainger, Z. Gultekin, M.
[8]
Lightowler, P. L. Spargo, J. Org. Chem. 1995, 60, 4962; V. K.
Aggarwal, Z. Gultekin, R. S. Grainger, H. Adams, P. L.
Spargo, J. Chem. Soc., Perkin Trans. 1 1998, 2771.
B. M. Trost, Y. Tamaru, J. Am. Chem. Soc. 1977, 99, 3101.
J. L. Boucher, L. Stella, Tetrahedron 1988, 44, 3595.
J. L. Boucher, L. Stella, Tetrahedron 1988, 44, 3607.
A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron: Asym-
metry 1998, 9, 1.
D. A. Evans, J. A. Murry, P. Vonmatt, R. D. Norcross, S. J.
Miller, Angew. Chem. Int. Ed. Engl. 1995, 34, 798.
D. A. Evans, S. J. Miller, T. Lectka, J. Am. Chem. Soc. 1993,
115, 6460.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
For a preliminary account see: V. K. Aggarwal, E. S. Anderson,
D. E. Jones, K. B. Obierey, R. Giles, Chem. Commun. 1998,
1985.
[16]
Other bisoxazolines tested include R ϭ iBu and Bn. These gave
low enantioselectivities at 0 °C (13% and 7%, respectively) and
were not tested further at low temperatures.
[17]
The acrylates (except 5 which was prepared by condensation
of tert-butyl-2-bromoacrylate with sodium thiophenolate, see
ref.[11]) were prepared from the corresponding sulfoxides by a
Pummerer reaction. See: J. Durman, J. I. Grayson, P. G. Hunt,
S. Warren, J. Chem. Soc., Perkin Trans. 1 1986, 1939Ϫ1945; H.
J. Monteiro, A. L. Gemal, Synthesis 1975, 437. Details of the
synthesis of trifluoroethyl acrylate 6 are presented in the experi-
mental section.
I. W. Davies, C. H. Senanayake, R. D. Larsen, T. R. Verhoeven,
P. J. Reider, Tetrahedron Lett. 1996, 37, 1725.
I. W. Davies, L. Gerena, D. W. Cai, R. D. Larsen, T. R. Verho-
even, P. J. Reider, Tetrahedron Lett. 1997, 38, 1145.
M. Johannsen, K. A. Jorgensen, J. Org. Chem. 1995, 60, 5757.
D. A. Evans, M. C. Kozlowski, C. S. Burgey, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 1997, 119, 7893.
Y. Honda, T. Date, H. Hiramatsu, M. Yamauchi, Chem. Com-
mun. 1997, 1411Ϫ1412.
D. A. Evans, T. Rovis, M. C. Kozlowski, J. S. Tedrow, J. Am.
Chem. Soc. 1999, 121, 1994.
(1S,4S)-Bicyclo-[2.2.1]-hept-5-ene-2-one (norbornenone) (15): A so-
lution of 4 (240 mg, 0.96 mmol) in acetonitrile (0.5 mL) was added
to a solution of diphenylphosphorylazide (272 mg, 0.96 mmol) and
triethylamine (97 mg, 0.96 mmol) in acetonitrile (4.0 mL) and water
(0.8 mL) and the solution refluxed for 23 h. Upon cooling to room
temperature, the reaction mixture was poured into aqueous
NaHCO3 (satd. 15 mL) and extracted with dichloromethane (4 ϫ
20 mL). The combined organic extracts were washed with aqueous
NH4Cl (3 ϫ 15 mL) and water (3 ϫ 15 mL), then dried over
MgSO4 and solvent removed under reduced pressure. Flash column
chromatography (pentane/diethyl ether 9:1) gave the title com-
[18]
[19]
[20]
[21]
[22]
[23]
1
pound as a sweet smelling, pale-yellow liquid (91 mg, 88%). Ϫ H
[24]
NMR (250 MHz, CDCl3) δ ϭ (endo ϩ exo) 1.72Ϫ1.96 (m, 3 H),
2.06Ϫ2.17 (m, 1 H), 2.90Ϫ2.97 (m, 1 H), 3.07Ϫ3.14 (m, 1 H),
K. Ninomiya, T. Shioiri, S. Yamada, Tetrahedron 1974, 30,
2151.
[25]
5.97Ϫ6.06 (m, 1 H), 6.47 (dd, J ϭ 5.0, 2.5 Hz, 1 H). Ϫ [α]2D2
ϭ
I. W. Davies, L. Gerena, L. Castonguay, C. H. Senanayake,
R. D. Larsen, T. R. Verhoeven, P. J. Reider, Chem. Commun.
Ϫ711 (c ϭ 0.15 in CHCl3) [ref.(1R,4R),[35] ϭ ϩ980 (c ϭ 0.3 in
1996, 1753.
CHCl3).
[26]
A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron Lett.
1996, 37, 3815.
[27]
For further discussion on the effect of geminal substituents on
The enantiomeric excess was determined by chiral GC analysis
which was carried out on a chiral cyclodextrin-α column (30 m,
0.25 mm i.d.), using hydrogen as the carrier gas at a flow rate of
16Psi, 70 °C isothermal, flame ionisation detection. (1R,4R)-(ϩ)-
15 had a retention time of 10.50 min while (1S,4S)-(Ϫ)-15 had a
retention time of 10.04. From GC analysis, (1S,4S)-(Ϫ)-15 was ob-
tained with 88% ee.
bite angle see: R. M. Beesley, C. K. Ingold, J. F. Thorpe, J.
Chem. Soc., 1915, 107, 1080; M. E. Jung, Synlett, 1999, 843.
[28]
D. A. Evans, J. S. Johnson, C. S. Burgey, K. R. Campos, Tetra-
hedron Lett. 1999, 40, 2879.
M. Johannsen, S. Yao, K. A. Jorgensen, Chem. Commun.
1997, 2169.
[29]
[30]
M. P. Sibi, J. Ji, J. Org. Chem. 1997, 62, 3800.
2944
Eur. J. Org. Chem. 2000, 2939Ϫ2945

Copper(II)-Bisoxazoline-Catalysed Asymmetric DielsϪAlder Reactions of α-Thioacrylates
FULL PAPER
[31]
A. K. Ghosh, P. Mathivanan, J. Cappiello, K. Krichnan, Tetra-
hedron: Asymmetry 1996, 7, 2165.
S. Yao, M. Johannsen, K. A. Jorgensen, J. Chem. Soc., Perkin
Trans. 1 1997, 2345.
D. A. Evans, M. C. Kozlowski, J. S. Tedrow, Tetrahedron Lett.
1996, 37, 7481.
also: A. E. Greene, C. L. Drian, J. Am. Chem. Soc. 1982,
104, 5473.
[32]
[33]
[36]
[37]
F. Theil, A. Kunath, M. Ramm, T. Reiher, H. Schick, J. Chem.
Soc., Perkin Trans 1, 1994, 11, 1509.
Y. Langlois, A. Pouihles, Tetrahedron: Asymmetry 1991, 2,
1223.
[34]
[35]
F. Leyendecker, M-T Comte, Tetrahedron Lett. 1982, 48, 5031.
E. J. Corey, T.-P. Loh, J. Am. Chem. Soc. 1991, 113, 8966. See
Received March 19, 2000
[O00135]
Eur. J. Org. Chem. 2000, 2939Ϫ2945
2945